Sequential Treatment with Intermittent Low-Dose Human Parathyroid Hormone (1-34) and Bisphosphonate Enhances Large-Size Skeletal Reconstruction by Vascularized Bone Transplantation

Abstract

Vascularized bone transplantation enables reconstruction of large skeletal defects, but this process needs a long time. Since short-term intermittent parathyroid hormone (PTH) enhances rat fracture healing, we investigated the effects of 4-week intermittent low-dose (10 microg/kg/day) or high-dose (100 microg/kg/day) PTH followed by 4-week vehicle, low-dose or high-dose intermittent PTH, or zoledronic acid (ZOL, 2 micro/kg/week), a potent bisphosphonate, on large skeletal reconstruction by vascularized tibial grafting in rats. Compared to 8-week vehicle, 8-week low-dose PTH did not significantly increase the serum osteocalcin level as well as the urinary deoxypyridinoline level, while 4-week low-dose or high-dose PTH followed by 4-week ZOL decreased both of these levels. Eight-week PTH increased the bone mass of the graft and strength of the reconstructed skeleton in a dose-dependent manner; notably, the reconstructed skeleton showed an obviously higher response to PTH compared to the contralateral nonoperated femur. In contrast, 4-week PTH followed by 4-week vehicle reduced these effects and caused local bone loss at the host-graft junctions. Four-week PTH followed by 4-week ZOL did not induce such bone loss; however, 4-week high-dose PTH followed by 4-week ZOL caused a large callus in the distal cortical junction. Four-week PTH followed by 4-week ZOL increased the bone mass and strength similarly to 8-week PTH. These preliminary findings suggest, for the first time, that sequential treatment with short-term intermittent low-dose PTH and bisphosphonate as well as long-term intermittent low-dose PTH treatment enhance large skeletal reconstruction by vascularized bone transplantation, though early timing of sequential antiresorptive treatment could result in delay of bone repair.

Aminobisphosphonate Stimulates Bone Regeneration and Enforces Consolidation of Titanium Implant into a New Rat Caudal Vertebrae Model

“…It can be hypothesized that deleterious side effects which may occur in the oral cavity during bisphosphonate therapy cannot be attributed exclusively to bisphosphonates, rather to the complex and multifactorial background of diseased patients, resulting in different and very changeable oral microflora. Indeed, an emerging notion indicates that the timing and single dosage schedules, influences the therapeutic efficacy and side effects due to the direct action of bisphosphonates on osteoclasts [40,41]. Taking available information from the literature and our results together, the data supports that bisphosphonates possess dual effects, acting both on bone building osteoblasts [28][29][30] and on bone resorbtion by osteoclasts [10,36,42].…”

The effects of combined human parathyroid hormone (1-34) and zoledronic acid treatment on fracture healing in osteoporotic rats

“…The dose rate at 60 μg/kg (three times a week) of PTH in this study was similar to that routinely used in rodent models [37,38] but much higher than therapeutic dose in patients (40-100 μg/day) [32,33]. Thus, the dose of PTH used in rodent animals is generally 20-100 times higher than the therapeutic dose used in humans based on body weight.…”

Teriparatide therapy enhances devitalized femoral allograft osseointegration and biomechanics in a murine model

“…Intermittent teriparatide treatment has been shown to increase the strength and bone mineral content in a rat model of freshly harvested, vascularized long bone allograft, either alone or when followed by treatment with the bisphosphonate zoledronic acid [36]. It has also been reported that intermittent administration of teriparatide accelerates rat spinal arthrodesis after autologous bone grafting [37].…”